Restricted Diffusion For Cytometry Research Articles

SsVERDICT: Self-supervised VERDICT-MRI for enhanced prostate tumor characterization.

Demonstrating and assessing self-supervised machine-learning fitting of the VERDICT (vascular, extracellular and restricted diffusion for cytometry in tumors) model for prostate cancer. We derive a self-supervised neural network for fitting VERDICT (ssVERDICT) that estimates parameter maps without training data. We compare the performance of ssVERDICT to two established baseline methods for fitting diffusion MRI models: conventional nonlinear least squares and supervised deep learning. We do this quantitatively on simulated data by comparing the Pearson's correlation coefficient, mean-squared error, bias, and variance with respect to the simulated ground truth. We also calculate in vivo parameter maps on a cohort of 20 prostate cancer patients and compare the methods' performance in discriminating benign from cancerous tissue via Wilcoxon's signed-rank test. In simulations, ssVERDICT outperforms the baseline methods (nonlinear least squares and supervised deep learning) in estimating all the parameters from the VERDICT prostate model in terms of Pearson's correlation coefficient, bias, and mean-squared error. In vivo, ssVERDICT shows stronger lesion conspicuity across all parameter maps, and improves discrimination between benign and cancerous tissue over the baseline methods. ssVERDICT significantly outperforms state-of-the-art methods for VERDICT model fitting and shows, for the first time, fitting of a detailed multicompartment biophysical diffusion MRI model with machine learning without the requirement of explicit training labels.

Advanced Diffusion-Weighted MRI for Cancer Microstructure Assessment in Body Imaging, and Its Relationship With Histology.

Diffusion-weighted magnetic resonance imaging (DW-MRI) aims to disentangle multiple biological signal sources in each imaging voxel, enabling the computation of innovative maps of tissue microstructure. DW-MRI model development has been dominated by brain applications. More recently, advanced methods with high fidelity to histology are gaining momentum in other contexts, for example, in oncological applications of body imaging, where new biomarkers are urgently needed. The objective of this article is to review the state-of-the-art of DW-MRI in body imaging (ie, not including the nervous system) in oncology, and to analyze its value as compared to reference colocalized histology measurements, given that demonstrating the histological validity of any new DW-MRI method is essential. In this article, we review the current landscape of DW-MRI techniques that extend standard apparent diffusion coefficient (ADC), describing their acquisition protocols, signal models, fitting settings, microstructural parameters, and relationship with histology. Preclinical, clinical, and in/ex vivo studies were included. The most used techniques were intravoxel incoherent motion (IVIM; 36.3% of used techniques), diffusion kurtosis imaging (DKI; 16.7%), vascular, extracellular, and restricted diffusion for cytometry in tumors (VERDICT; 13.3%), and imaging microstructural parameters using limited spectrally edited diffusion (IMPULSED; 11.7%). Another notable category of techniques relates to innovative b-tensor diffusion encoding or joint diffusion-relaxometry. The reviewed approaches provide histologically meaningful indices of cancer microstructure (eg, vascularization/cellularity) which, while not necessarily accurate numerically, may still provide useful sensitivity to microscopic pathological processes. Future work of the community should focus on improving the inter-/intra-scanner robustness, and on assessing histological validity in broader contexts. LEVEL OF EVIDENCE: NA TECHNICAL EFFICACY: Stage 2.

Prostate MR image quality of apparent diffusion coefficient maps versus fractional intracellular volume maps from VERDICT MRI using the PI-QUAL score and a dedicated Likert scale for artefacts

PurposeThis study aimed to assess the image quality of apparent diffusion coefficient (ADC) maps derived from conventional diffusion-weighted MRI and fractional intracellular volume maps (FIC) from VERDICT MRI (Vascular, Extracellular, Restricted Diffusion for Cytometry in Tumours) in patients from the INNOVATE trial. The inter-reader agreement was also assessed. MethodsTwo readers analysed both ADC and FIC maps from 57 patients enrolled in the INNOVATE prospective trial. Image quality was assessed using the Prostate Imaging Quality (PI-QUAL) score and a subjective image quality Likert score (Likert-IQ). The image quality of FIC and ADC were compared using a Wilcoxon Signed Ranks test. The inter-reader agreement was assessed with Cohen’s kappa. ResultsThere was no statistically significant difference between the PI-QUAL score for FIC datasets compared to ADC datasets for either reader (p = 0.240 and p = 0.614). Using the Likert-IQ score, FIC image quality was higher compared to ADC (p = 0.021) as assessed by reader-1 but not for reader-2 (p = 0.663). The inter-reader agreement was ‘fair’ for PI-QUAL scoring of datasets with FIC maps at 0.27 (95% confidence interval; 0.08–0.46) and ADC datasets at 0.39 (95% confidence interval 0.22–0.57). For Likert scoring, the inter-reader agreement was also ‘fair’ for FIC maps at 0.38 (95% confidence interval; 0.10–0.65) and substantial for ADC maps at 0.62 (95% confidence interval; 0.39–0.86). ConclusionImage quality was comparable for FIC and ADC. The inter-reader agreement was similar when using PIQUAL for both FIC and ADC datasets but higher for ADC maps compared to FIC maps using the image quality Likert score.

Test-retest repeatability of ADC in prostate using the multi b-Value VERDICT acquisition

PurposeVERDICT (Vascular, Extracellular, Restricted Diffusion for Cytometry in Tumours) MRI is a multi b-value, variable diffusion time DWI sequence that allows generation of ADC maps from different b-value and diffusion time combinations. The aim was to assess precision of prostate ADC measurements from varying b-value combinations using VERDICT and determine which protocol provides the most repeatable ADC. Materials and MethodsForty-one men (median age: 67.7 years) from a prior prospective VERDICT study (April 2016–October 2017) were analysed retrospectively. Men who were suspected of prostate cancer and scanned twice using VERDICT were included. ADC maps were formed using 5b-value combinations and the within-subject standard deviations (wSD) were calculated per ADC map. Three anatomical locations were analysed per subject: normal TZ (transition zone), normal PZ (peripheral zone), and index lesions. Repeated measures ANOVAs showed which b-value range had the lowest wSD, Spearman correlation and generalized linear model regression analysis determined whether wSD was related to ADC magnitude and ROI size. ResultsThe mean lesion ADC for b0b1500 had the lowest wSD in most zones (0.18–0.58x10-4 mm2/s). The wSD was unaffected by ADC magnitude (Lesion: p = 0.064, TZ: p = 0.368, PZ: p = 0.072) and lesion Likert score (p = 0.95). wSD showed a decrease with ROI size pooled over zones (p = 0.019, adjusted regression coefficient = -1.6x10-3, larger ROIs for TZ versus PZ versus lesions). ADC maps formed with a maximum b-value of 500 s/mm2 had the largest wSDs (1.90–10.24x10-4 mm2/s). ConclusionADC maps generated from b0b1500 have better repeatability in normal TZ, normal PZ, and index lesions.

Joint estimation of relaxation and diffusion tissue parameters for prostate cancer with relaxation-VERDICT MRI

This work presents a biophysical model of diffusion and relaxation MRI for prostate called relaxation vascular, extracellular and restricted diffusion for cytometry in tumours (rVERDICT). The model includes compartment-specific relaxation effects providing T1/T2 estimates and microstructural parameters unbiased by relaxation properties of the tissue. 44 men with suspected prostate cancer (PCa) underwent multiparametric MRI (mp-MRI) and VERDICT-MRI followed by targeted biopsy. We estimate joint diffusion and relaxation prostate tissue parameters with rVERDICT using deep neural networks for fast fitting. We tested the feasibility of rVERDICT estimates for Gleason grade discrimination and compared with classic VERDICT and the apparent diffusion coefficient (ADC) from mp-MRI. The rVERDICT intracellular volume fraction fic discriminated between Gleason 3 + 3 and 3 + 4 (p = 0.003) and Gleason 3 + 4 and ≥ 4 + 3 (p = 0.040), outperforming classic VERDICT and the ADC from mp-MRI. To evaluate the relaxation estimates we compare against independent multi-TE acquisitions, showing that the rVERDICT T2 values are not significantly different from those estimated with the independent multi-TE acquisition (p > 0.05). Also, rVERDICT parameters exhibited high repeatability when rescanning five patients (R2 = 0.79–0.98; CV = 1–7%; ICC = 92–98%). The rVERDICT model allows for accurate, fast and repeatable estimation of diffusion and relaxation properties of PCa sensitive enough to discriminate Gleason grades 3 + 3, 3 + 4 and ≥ 4 + 3.

Emerging MR methods for improved diagnosis of prostate cancer by multiparametric MRI.

Current challenges of using serum prostate-specific antigen (PSA) level-based screening, such as the increased false positive rate, inability to detect clinically significant prostate cancer (PCa) with random biopsy, multifocality in PCa, and the molecular heterogeneity of PCa, can be addressed by integrating advanced multiparametric MR imaging (mpMRI) approaches into the diagnostic workup of PCa. The standard method for diagnosing PCa is a transrectal ultrasonography (TRUS)-guided systematic prostate biopsy, but it suffers from sampling errors and frequently fails to detect clinically significant PCa. mpMRI not only increases the detection of clinically significant PCa, but it also helps to reduce unnecessary biopsies because of its high negative predictive value. Furthermore, non-Cartesian image acquisition and compressed sensing have resulted in faster MR acquisition with improved signal-to-noise ratio, which can be used in quantitative MRI methods such as dynamic contrast-enhanced (DCE)-MRI. With the growing emphasis on the role of pre-biopsy mpMRI in the evaluation of PCa, there is an increased demand for innovative MRI methods that can improve PCa grading, detect clinically significant PCa, and biopsy guidance. To meet these demands, in addition to routine T1-weighted, T2-weighted, DCE-MRI, diffusion MRI, and MR spectroscopy, several new MR methods such as restriction spectrum imaging, vascular, extracellular, and restricted diffusion for cytometry in tumors (VERDICT) method, hybrid multi-dimensional MRI, luminal water imaging, and MR fingerprinting have been developed for a better characterization of the disease. Further, with the increasing interest in combining MR data with clinical and genomic data, there is a growing interest in utilizing radiomics and radiogenomics approaches. These big data can also be utilized in the development of computer-aided diagnostic tools, including automatic segmentation and thedetection of clinically significantPCa using machine learning methods.

Differentiating False Positive Lesions from Clinically Significant Cancer and Normal Prostate Tissue Using VERDICT MRI and Other Diffusion Models.

False positives on multiparametric MRIs (mp-MRIs) result in many unnecessary invasive biopsies in men with clinically insignificant diseases. This study investigated whether quantitative diffusion MRI could differentiate between false positives, true positives and normal tissue non-invasively. Thirty-eight patients underwent mp-MRI and Vascular, Extracellular and Restricted Diffusion for Cytometry in Tumors (VERDICT) MRI, followed by transperineal biopsy. The patients were categorized into two groups following biopsy: (1) significant cancer—true positive, 19 patients; (2) atrophy/inflammation/high-grade prostatic intraepithelial neoplasia (PIN)—false positive, 19 patients. The clinical apparent diffusion coefficient (ADC) values were obtained, and the intravoxel incoherent motion (IVIM), diffusion kurtosis imaging (DKI) and VERDICT models were fitted via deep learning. Significant differences (p < 0.05) between true positive and false positive lesions were found in ADC, IVIM perfusion fraction (f) and diffusivity (D), DKI diffusivity (DK) (p < 0.0001) and kurtosis (K) and VERDICT intracellular volume fraction (fIC), extracellular–extravascular volume fraction (fEES) and diffusivity (dEES) values. Significant differences between false positives and normal tissue were found for the VERDICT fIC (p = 0.004) and IVIM D. These results demonstrate that model-based diffusion MRI could reduce unnecessary biopsies occurring due to false positive prostate lesions and shows promising sensitivity to benign diseases.

VERDICT MRI for radiation treatment response assessment in neuroendocrine tumors.

Noninvasive methods to study changes in tumor microstructure enable early assessment of treatment response and thus facilitate personalized treatment. The aim of this study was to evaluate the diffusion MRI model, Vascular, Extracellular and Restricted Diffusion for Cytometry in Tumors (VERDICT), for early response assessment to external radiation treatment and to compare the results with those of more studied sets of parameters derived from diffusion-weighted MRI data. Mice xenografted with human small intestine tumors were treated with external radiation treatment, and diffusion MRI experiments were performed on the day before and up to 2 weeks after treatment. The diffusion models VERDICT, ADC, IVIM, and DKI were fitted to MRI data, and the treatment response of each tumor was calculated based on pretreatment tumor growth and post-treatment tumor volume regression. Linear regression and correlation analysis were used to evaluate each model and their respective parameters for explaining the treatment response. VERDICT analysis showed significant changes from day -1 to day 3 for the intracellular and extracellular volume fraction, as well as the cell radius index (p<0.05; Wilcoxon signed-rank test). The strongest correlation between the diffusion model parameters and the tumor treatment response was seen for the ADC, kurtosis-corrected diffusion coefficient, and intracellular volume fraction on day 3 (τ =0.47, 0.52, and -0.49, respectively, p<0.05; Kendall rank correlation coefficient). Of all the tested models, VERDICT held the strongest explanatory value for the tumor treatment response on day 3 (R2 =0.75, p<0.01; linear regression). In conclusion, VERDICT has potential for early assessment of external radiation treatment and may provide further insights into the underlying biological effects of radiation on tumor tissue. In addition, the results suggest that the time window for assessment of treatment response using dMRI may be narrow.

Emerging methods for prostate cancer imaging: evaluating cancer structure and metabolic alterations more clearly.

Imaging plays a fundamental role in all aspects of the cancer management pathway. However, conventional imaging techniques are largely reliant on morphological and size descriptors that have well‐known limitations, particularly when considering targeted‐therapy response monitoring. Thus, new imaging methods have been developed to characterise cancer and are now routinely implemented, such as diffusion‐weighted imaging, dynamic contrast enhancement, positron emission technology (PET) and magnetic resonance spectroscopy. However, despite the improvement these techniques have enabled, limitations still remain. Novel imaging methods are now emerging, intent on further interrogating cancers. These techniques are at different stages of maturity along the biomarker pathway and aim to further evaluate the cancer microstructure (vascular, extracellular and restricted diffusion for cytometry in tumours) magnetic resonance imaging (MRI), luminal water fraction imaging] as well as the metabolic alterations associated with cancers (novel PET tracers, hyperpolarised MRI). Finally, the use of machine learning has shown powerful potential applications. By using prostate cancer as an exemplar, this Review aims to showcase these potentially potent imaging techniques and what stage we are at in their application to conventional clinical practice.

Multiparametric MRI in the Diagnosis of Prostate Cancer: Physical Foundations, Limitations, and Prospective Advances ofDiffusion-Weighted MRI.

Diffusion-weighted imaging (DWI) is an essential component of the multiparametric MRI exam for the diagnosis and assessment of prostate cancer (PCa). Over the last two decades, various models have been developed to quantitatively correlate the DWI signal with microstructural characteristics of prostate tissue. The simplest approach (ADC: apparent diffusion coefficient) - currently established as the clinical standard - describes monoexponential decay of the DWI signal. While numerous studies have shown an inverse correlation of ADC values with the Gleason score, the ADC model lacks specificity and is based on water diffusion dynamics that are not true in human tissue. This article aims to explain the biophysical limitations of the standard DWI model and to discuss the potential of more complex, advanced DWI models. This article is a review based on a selective literature review. Four phenomenological DWI models are introduced: diffusion tensor imaging, intravoxel incoherent motion, biexponential model, and diffusion kurtosis imaging. Their parameters may potentially improve PCa diagnostics but show varying degrees of statistical significance with respect to the detection and characterization of PCa in current studies. Phenomenological model parameters lack specificity, which has motivated the development of more descriptive tissue models that directly relate microstructural features to the DWI signal. Finally, we present two of such structural models, i. e. the VERDICT (Vascular, Extracellular, and Restricted Diffusion for Cytometry in Tumors) and RSI (Restriction Spectrum Imaging) model. Both have shown promising results in initial studies regarding the characterization and prognosis of PCa. Recent developments in DWI techniques promise increasing accuracy and more specific statements about microstructural changes of PCa. However, further studies are necessary to establish a standardized DWI protocol for the diagnosis of PCa. · DWI is paramount to the mpMRI exam for the diagnosis of PCa.. · Though of clinical value, the ADC model lacks specificity and oversimplifies tissue complexities.. · Advanced phenomenological and structural models have been developed to describe the DWI signal.. · Phenomenological models may improve diagnostics but show inconsistent results regarding PCa assessment.. · Structural models have demonstrated promising results in initial studies regarding PCa characterization.. · Wichtmann BD, Zöllner FG, Attenberger UI et al. Multiparametric MRI in the Diagnosis of Prostate Cancer: Physical Foundations, Limitations, and Prospective Advances of Diffusion-Weighted MRI. Fortschr Röntgenstr 2021; 193: 399 - 409.

Noninvasive diffusion magnetic resonance imaging of brain tumour cell size for the early detection of therapeutic response

Cancer cells differ in size from those of their host tissue and are known to change in size during the processes of cell death. A noninvasive method for monitoring cell size would be highly advantageous as a potential biomarker of malignancy and early therapeutic response. This need is particularly acute in brain tumours where biopsy is a highly invasive procedure. Here, diffusion MRI data were acquired in a GL261 glioma mouse model before and during treatment with Temozolomide. The biophysical model VERDICT (Vascular Extracellular and Restricted Diffusion for Cytometry in Tumours) was applied to the MRI data to quantify multi-compartmental parameters connected to the underlying tissue microstructure, which could potentially be useful clinical biomarkers. These parameters were compared to ADC and kurtosis diffusion models, and, measures from histology and optical projection tomography. MRI data was also acquired in patients to assess the feasibility of applying VERDICT in a range of different glioma subtypes. In the GL261 gliomas, cellular changes were detected according to the VERDICT model in advance of gross tumour volume changes as well as ADC and kurtosis models. VERDICT parameters in glioblastoma patients were most consistent with the GL261 mouse model, whilst displaying additional regions of localised tissue heterogeneity. The present VERDICT model was less appropriate for modelling more diffuse astrocytomas and oligodendrogliomas, but could be tuned to improve the representation of these tumour types. Biophysical modelling of the diffusion MRI signal permits monitoring of brain tumours without invasive intervention. VERDICT responds to microstructural changes induced by chemotherapy, is feasible within clinical scan times and could provide useful biomarkers of treatment response.

Age-related and zonal anatomical microstructure features of normal prostatic tissues: a preliminary study with VERDICT MRI.

This study aimed to explore the differences in VERDICT parameters for normal prostatic tissues among different regions and age groups. In total, 31 male volunteers were included in the study. Vascular, extracellular and restricted diffusion for cytometry in tumors (VERDICT) model parameters (fIC, intracellular volume fraction; fEES, extracellular-extravascular space fraction; and fVASC, vascular fraction) were calculated based on the whole prostate volume and the peripheral zone (PZ), central gland (CG) and anterior fibromuscular stroma(AS) regions of interest (ROIs). Agreement between two readers was determined by calculating the intraclass correlation coefficient. Two-way ANOVA was used to identify significant differences among age groups and regions within the prostate. Age-related and area-related changes in these parameters were assessed using Spearman's correlation coefficients. There were differences in the parameters among regions of the prostate (P < 0.05). In the PZ, there was a negative correlation between age and fIC (r = - 0.66, P < 0.001, adjusted P < 0.001), and age was positively correlated with fEES (r = 0.69, P < 0.001, adjusted P < 0.001) but had no correlation with fVASC. In the CG ROI, there was a positive correlation between age and fEES (r = 0.56, P < 0.001, adjusted P < 0.001) but no correlation between age and fVASC, similar to the results for the PZ. There were no correlations between age and VERDICT parameters in the AS. VERDICT parameters vary among different regions of the prostate and correlate with age. These findings are in agreement with histological theory.

VERDICT MRI for Prostate Cancer: Intracellular Volume Fraction versus Apparent Diffusion Coefficient.

BackgroundBiologic specificity of diffusion MRI in relation to prostate cancer aggressiveness may improve by examining separate components of the diffusion MRI signal. The Vascular, Extracellular, and Restricted Diffusion for Cytometry in Tumors (VERDICT) model estimates three distinct signal components and associates them to (a) intracellular water, (b) water in the extracellular extravascular space, and (c) water in the microvasculature.PurposeTo evaluate the repeatability, image quality, and diagnostic utility of intracellular volume fraction (FIC) maps obtained with VERDICT prostate MRI and to compare those maps with apparent diffusion coefficient (ADC) maps for Gleason grade differentiation.Materials and MethodsSeventy men (median age, 62.2 years; range, 49.5–82.0 years) suspected of having prostate cancer or undergoing active surveillance were recruited to a prospective study between April 2016 and October 2017. All men underwent multiparametric prostate and VERDICT MRI. Forty-two of the 70 men (median age, 67.7 years; range, 50.0–82.0 years) underwent two VERDICT MRI acquisitions to assess repeatability of FIC measurements obtained with VERDICT MRI. Repeatability was measured with use of intraclass correlation coefficients (ICCs). The image quality of FIC and ADC maps was independently evaluated by two board-certified radiologists. Forty-two men (median age, 64.8 years; range, 49.5–79.6 years) underwent targeted biopsy, which enabled comparison of FIC and ADC metrics in the differentiation between Gleason grades.ResultsVERDICT MRI FIC demonstrated ICCs of 0.87–0.95. There was no significant difference between image quality of ADC and FIC maps (score, 3.1 vs 3.3, respectively; P = .90). FIC was higher in lesions with a Gleason grade of at least 3+4 compared with benign and/or Gleason grade 3+3 lesions (mean, 0.49 ± 0.17 vs 0.31 ± 0.12, respectively; P = .002). The difference in ADC between these groups did not reach statistical significance (mean, 1.42 vs 1.16 × 10-3 mm2/sec; P = .26).ConclusionFractional intracellular volume demonstrates high repeatability and image quality and enables better differentiation of a Gleason 4 component cancer from benign and/or Gleason 3+3 histology than apparent diffusion coefficient.Published under a CC BY 4.0 license.Online supplemental material is available for this article.See also the editorial by Sigmund and Rosenkrantz in this issue.

Non-invasive assessment of glioma microstructure using VERDICT MRI: correlation with histology

PurposeThis prospective study evaluated the use of vascular, extracellular and restricted diffusion for cytometry in tumours (VERDICT) MRI to investigate the tissue microstructure in glioma. VERDICT-derived parameters were correlated with both histological features and tumour subtype and were also used to explore the peritumoural region.MethodsFourteen consecutive treatment-naïve patients (43.5 years ± 15.1 years, six males, eight females) with suspected glioma underwent diffusion-weighted imaging including VERDICT modelling. Tumour cell radius and intracellular and combined extracellular/vascular volumes were estimated using a framework based on linearisation and convex optimisation. An experienced neuroradiologist outlined the peritumoural oedema, enhancing tumour and necrosis on T2-weighted imaging and contrast-enhanced T1-weighted imaging. The same regions of interest were applied to the co-registered VERDICT maps to calculate the microstructure parameters. Pathology sections were analysed with semi-automated software to measure cellularity and cell size.ResultsVERDICT parameters were successfully calculated in all patients. The imaging-derived results showed a larger intracellular volume fraction in high-grade glioma compared to low-grade glioma (0.13 ± 0.07 vs. 0.08 ± 0.02, respectively; p = 0.05) and a trend towards a smaller extracellular/vascular volume fraction (0.88 ± 0.07 vs. 0.92 ± 0.04, respectively; p = 0.10). The conventional apparent diffusion coefficient was higher in low-grade gliomas compared to high-grade gliomas, but this difference was not statistically significant (1.22 ± 0.13 × 10−3 mm2/s vs. 0.98 ± 0.38 × 10−3 mm2/s, respectively; p = 0.18).ConclusionThis feasibility study demonstrated that VERDICT MRI can be used to explore the tissue microstructure of glioma using an abbreviated protocol. The VERDICT parameters of tissue structure correlated with those derived on histology. The method shows promise as a potential test for diagnostic stratification and treatment response monitoring in the future.Key Points• VERDICT MRI is an advanced diffusion technique which has been correlated with histopathological findings obtained at surgery from patients with glioma in this study.• The intracellular volume fraction measured with VERDICT was larger in high-grade tumours compared to that in low-grade tumours.• The results were complementary to measurements from conventional diffusion-weighted imaging, and the technique could be performed in a clinically feasible timescale.

Simplified Luminal Water Imaging for the Detection of Prostate Cancer From Multiecho T2 MR Images.

BackgroundLuminal water imaging (LWI) suffers less from imaging artifacts than the diffusion‐weighted imaging used in multiparametric MRI of the prostate. LWI obtains multicompartment tissue information from a multiecho T2 dataset.PurposeTo compare a simplified LWI technique with apparent diffusion coefficient (ADC) in classifying lesions based on groupings of PI‐RADS v2 scores. Secondary aims were to investigate whether LWI differentiates between histologically confirmed tumor and normal tissue as effectively as ADC, and whether LWI is correlated with the multicompartment parameters of the vascular, extracellular, and restricted diffusion for cytometry in tumors (VERDICT) diffusion model.Study TypeA subset of a larger prospective study.PopulationIn all, 65 male patients aged 49–79 were scanned.Field Strength/SequenceA 32‐echo T2 and a six b‐value diffusion sequence (0, 90, 500, 1500, 2000, 3000 s/mm2) at 3T.AssessmentRegions of interest were placed by a board‐certified radiologist in areas of lesion and benign tissue and given PI‐RADS v2 scores.Statistical TestsReceiver operating characteristic and logistic regression analyses were performed.ResultsLWI classifies tissue as PI‐RADS 1,2 or PI‐RADS 3,4,5 with an area under curve (AUC) value of 0.779, compared with 0.764 for ADC. LWI differentiated histologically confirmed malignant from nonmalignant tissue with AUC, sensitivity, and specificity values of 0.81, 75%, and 87%, compared with 0.75, 83%, and 67% for ADC. The microstructural basis of the LWI technique is further suggested by the correspondence with the VERDICT diffusion‐based microstructural imaging technique, with α, A 1 , A 2, and LWF showing significant correlations.Data ConclusionLWI alone can predict PI‐RADS v2 score groupings and detect histologically confirmed tumors with an ability similar to ADC alone without the limitations of diffusion‐weighted MRI. This is important, given that ADC has an advantage in these tests as it already informs PI‐RADS v2 scoring. LWI also provides multicompartment information that has an explicit biophysical interpretation, unlike ADC. Level of Evidence: 3 Technical Efficacy: Stage 2J. Magn. Reson. Imaging 2019;50:910–917.

VERDICT-AMICO: Ultrafast fitting algorithm for non-invasive prostate microstructure characterization.

VERDICT (vascular, extracellular and restricted diffusion for cytometry in tumours) estimates and maps microstructural features of cancerous tissue non‐invasively using diffusion MRI. The main purpose of this study is to address the high computational time of microstructural model fitting for prostate diagnosis, while retaining utility in terms of tumour conspicuity and repeatability.In this work, we adapt the accelerated microstructure imaging via convex optimization (AMICO) framework to linearize the estimation of VERDICT parameters for the prostate gland. We compare the original non‐linear fitting of VERDICT with the linear fitting, quantifying accuracy with synthetic data, and computational time and reliability (performance and precision) in eight patients. We also assess the repeatability (scan‐rescan) of the parameters.Comparison of the original VERDICT fitting versus VERDICT‐AMICO showed that the linearized fitting (1) is more accurate in simulation for a signal‐to‐noise ratio of 20 dB; (2) reduces the processing time by three orders of magnitude, from 6.55 seconds/voxel to 1.78 milliseconds/voxel; (3) estimates parameters more precisely; (4) produces similar parametric maps and (5) produces similar estimated parameters with a high Pearson correlation between implementations, r 2 > 0.7. The VERDICT‐AMICO estimates also show high levels of repeatability. Finally, we demonstrate that VERDICT‐AMICO can estimate an extra diffusivity parameter without losing tumour conspicuity and retains the fitting advantages.VERDICT‐AMICO provides microstructural maps for prostate cancer characterization in seconds.

Microstructure Characterization of Bone Metastases from Prostate Cancer with Diffusion MRI: Preliminary Findings.

To examine the usefulness of rich diffusion protocols with high b-values and varying diffusion time for probing microstructure in bone metastases. Analysis techniques including biophysical and mathematical models were compared with the clinical apparent diffusion coefficient (ADC). Four patients were scanned using 13 b-values up to 3,000 s/mm2 and diffusion times ranging 18-52 ms. Data were fitted to mono-exponential ADC, intravoxel incoherent motion (IVIM), Kurtosis and Vascular, extracellular, and restricted diffusion for cytometry in tumors (VERDICT) models. Parameters from the models were compared using correlation plots. ADC and IVIM did not fit the data well, failing to capture the signal at high b-values. The Kurtosis model best explained the data in many voxels, but in voxels exhibiting a more time-dependent signal, the VERDICT model explained the data best. The ADC correlated significantly (p < 0.004) with the intracellular diffusion coefficient (r = 0.48), intracellular volume fraction (r = -0.21), and perfusion fraction (r = 0.46) parameters from VERDICT, suggesting that these factors all contribute to ADC contrast. The mean kurtosis correlated with the intracellular volume fraction parameter (r = 0.26) from VERDICT, consistent with the hypothesis that kurtosis relates to cellularity, but also correlated weakly with the intracellular diffusion coefficient (r = 0.18) and cell radius (r = 0.16) parameters, suggesting that it may be difficult to attribute physical meaning to kurtosis. Both Kurtosis and VERDICT explained the diffusion signal better than ADC and IVIM, primarily due to poor fitting at high b-values in the latter two models. The Kurtosis and VERDICT models captured information at high b using parameters (Kurtosis or intracellular volume fraction and radius) that do not have a simple relationship with ADC and that may provide additional microstructural information in bone metastases.

Microstructural characterization of normal and malignant human prostate tissue with vascular, extracellular, and restricted diffusion for cytometry in tumours magnetic resonance imaging.

The aim of this study was to demonstrate the feasibility of the recently introduced Vascular, Extracellular, and Restricted Diffusion for Cytometry in Tumours (VERDICT) framework for imaging prostate cancer with diffusion-weighted magnetic resonance imaging (DW-MRI) within a clinical setting. The VERDICT framework is a noninvasive microstructure imaging technique that combines an in-depth diffusion MRI acquisition with a mathematical model to estimate and map microstructural tissue parameters such as cell size and density and vascular perfusion. In total, 8 patients underwent 3-T MRI using 9 different b values (100-3000 s/mm). All patients were imaged before undergoing biopsy. Experiments with VERDICT analyzed DW-MRI data from patients with histologically confirmed prostate cancer in areas of cancerous and benign peripheral zone tissue. For comparison, we also fitted commonly used diffusion models such as the apparent diffusion coefficient (ADC), the intravoxel incoherent motion (IVIM), and the kurtosis model. We also investigated correlations of ADC and kurtosis with VERDICT parameters to gain some biophysical insight into the various parameter values. Eight patients had prostate cancer in the peripheral zone, with Gleason score 3 + 3 (n = 1), 3 + 4 (n = 6), and 4 + 3 (n = 1). The VERDICT model identified a significant increase in the intracellular and vascular volume fraction estimates in cancerous compared with benign peripheral zone, as well as a significant decrease in the volume of the extracellular-extravascular space (EES) (P = 0.05). This is in agreement with manual segmentation of the biopsies for prostate tissue component analysis, which found proliferation of epithelium, loss of surrounding stroma, and an increase in vasculature. The standard ADC and kurtosis parameters were also significantly different (P = 0.05) between tissue types. There was no significant difference in any of the IVIM parameters (P = 0.11 to 0.29). The VERDICT parametric maps from voxel-by-voxel fitting clearly differentiated cancer from benign regions. Kurtosis and ADC parameters correlated most strongly with VERDICT's intracellular volume fraction but also moderately with the EES and vascular fractions. The VERDICT model distinguished tumor from benign areas, while revealing differences in microstructure descriptors such as cellular, vascular, and EES fractions. The parameters of ADC and kurtosis models also discriminated between cancer and benign regions. However, VERDICT provides more specific information that disentangles the various microstructural features underlying the changes in ADC and kurtosis. These results highlight the clinical potential of the VERDICT framework and motivate the construction of a shorter, clinically viable imaging protocol to enable larger trials leading to widespread translation of the method.

Noninvasive Quantification of Solid Tumor Microstructure Using VERDICT MRI

There is a need for biomarkers that are useful for noninvasive imaging of tumor pathophysiology and drug efficacy. Through its use of endogenous water, diffusion-weighted MRI (DW-MRI) can be used to probe local tissue architecture and structure. However, most DW-MRI studies of cancer tissues have relied on simplistic mathematical models, such as apparent diffusion coefficient (ADC) or intravoxel incoherent motion (IVIM) models, which produce equivocal results on the relation of the model parameter estimate with the underlying tissue microstructure. Here, we present a novel technique called VERDICT (Vascular, Extracellular and Restricted Diffusion for Cytometry in Tumors) to quantify and map histologic features of tumors in vivo. VERDICT couples DW-MRI to a mathematical model of tumor tissue to access features such as cell size, vascular volume fraction, intra- and extracellular volume fractions, and pseudo-diffusivity associated with blood flow. To illustrate VERDICT, we used two tumor xenograft models of colorectal cancer with different cellular and vascular phenotypes. Our experiments visualized known differences in the tissue microstructure of each model and the significant decrease in cell volume resulting from administration of the cytotoxic drug gemcitabine, reflecting the apoptotic volume decrease. In contrast, the standard ADC and IVIM models failed to detect either of these differences. Our results illustrate the superior features of VERDICT for cancer imaging, establishing it as a noninvasive method to monitor and stratify treatment responses.